Methylnaltrexone (MNTX) is a quaternary derivative of the opioid antagonist, naltrexone. MNTX exists as a salt, for example, a bromide salt. The bromide salt of MNTX is also known in the literature as: Methylnaltrexone bromide; N-Methylnaltrexone bromide; Naltrexone methobromide; Naltrexone methyl bromide; MRZ 2663BR. MNTX was first reported in the mid-70s by Goldberg et al. as described in U.S. Pat. No. 4,176,186. It is believed that addition of the methyl group to the ring nitrogen of naltrexone forms a charged compound with greater polarity and less liposolubility than naltrexone, preventing MNTX from crossing the blood-brain barrier in humans. As a consequence, MNTX exerts its effects in the periphery rather than in the central nervous system with the advantage that it does not counteract the analgesic effects of opioids on the central nervous system.
MNTX is a chiral molecule, wherein the quaternary nitrogen can possess either the (R) or (S) configuration. For example, (R)-MNTX refers to a molecule of MNTX having (R) stereochemistry at the quaternary nitrogen, while (S)-MNTX refers to a molecule of MNTX having (S) stereochemistry at the quaternary nitrogen. All of the reported functions of MNTX described in the literature indicate it is a peripheral opioid antagonist. Some of these antagonist functions are described in U.S. Pat. Nos. 4,176,186, 4,719,215, 4,861,781, 5,102,887, 5,972,954, 6,274,591, 6,559,158, and 6,608,075, and in U.S. patent application publication numbers 2003/0022909A1, 20040266806, 20040259899 and 20050004155. These uses include reducing the side-effects of opioids without reducing the analgesic effect of opioids. Such side-effects include nausea, emesis, dysphoria, pruritus, urinary retention, bowel hypomotility, constipation, gastric hypomotility, delayed gastric emptying and immune suppression. The art discloses that MNTX not only reduces the side-effects stemming from opioid analgesic treatment but also reduces the side-effects mediated by endogenous opioids alone (or in conjunction with exogenous opioid treatment) such as gastrointestinal dysfunction including inhibition of gastric emptying, constipation, inhibition of gastrointestinal motility from any cause such as surgery, inflammation or excessive vagal stimulation and other such conditions including, but not limited to, those mentioned above. However, it is unclear from the art whether the MNTX used in these studies was a mixture of (R) and (S) stereoisomers or a single stereoisomer.
The art suggests that isolated stereoisomers of a compound sometimes may have contrasting physical and functional properties, although it is unpredictable in any particular circumstance. Quaternary narcotic antagonists exhibit such contrasting physical and functional properties, making it important to develop procedures to isolate and identify MNTX as pure (R)-MNTX or (S)-MNTX. Goldberg, et al.'s U.S. Pat. No. 4,176,186, and more recently Cantrell, et al.'s WO 2004/043964 A2 describe a protocol for the synthesis of MNTX involving the quatemization of a tertiary N-substituted morphinan alkaloid with a methylating agent. However, both Goldberg et al and Cantrell et al remain silent as to the stereoisomer(s) produced by the synthesis. Based on the method of synthesis described in each, it is unknown whether the MNTX so produced was either (R) or (S) or a mixture of both. Furthermore, (S)—N-methylnaltrexone ((S)-MNTX), in pure form, and a method of making pure (S)-MNTX had not been described in the literature. Therefore, researchers would have been unable to definitively characterize and distinguish the stereoisomer(s) obtained by the Goldberg et al or Cantrell et al synthesis in the absence of pure (S)-MNTX as a standard.
In addition to the isolation and characterization of each stereoisomer of quaternary narcotic antagonists, it can be desirable to isolate the antagonists from any additional impurities in the manufacture of a pharmaceutical composition. Generally, pharmaceutical compositions also require a high level of purity to meet regulated standards for drug quality and purity. For example, in the synthesis of MNTX as described above, impurities are often formed, including degradants or by-products of manufacture, which may hinder the therapeutic effects of MNTX and/or may be toxic if present in high enough quantity. As such, it is desirable to have the ability to determine both the stereochemical configuration and the purity of MNTX. To do this, it is important to identify, isolate, and chemically characterize impurities, which can be used in chromatographic procedures as standards to confirm the purity of MNTX.